Sepsis causes major metabolic alterations in both overt and latent diabetics, resulting in metabolic decompensation and greater reliance on exogenously administered insulin. The septic non-diabetic patient depends heavily on carbohydrates, yet carbohydrate homeostasis is markedly altered by sepsis. The proposed studies will test three hypotheses: 1) alterations in carbohydrate homeostasis are in part responsible for the deterioration of the animal subjected to Gram-negative infection, 2) the septic animal is not capable of maintaining adequate carbohydrate reserves which renders it less able to meet the increased metabolic demands imposed by Gramnegative infection, and 3) the inability of latent or overt diabetic animals to maintain glycogen reserves and carbohydrate homeostasis are responsible for the increased morbidity and mortality of diabetics to sepsis. The primary aim of this project is to elucidate the etiology of altered carbohydrate homeostasis during a persistent septic state in non-diabetic, latent diabetic, overt diabetic and overt diabetic insulin treated rats. This aim will be accomplished by investigating the progression of changes in glucose kinetics (turnover, clearance, recycling), glycogenolysis (hepatic and extrahepatic), glycogen synthesis, gluconeogenesis and glycogen replenishment. These aspects of carbohydrate metabolism will be studied in chronically catheterized nondiabetic and diabetic conscious rats. The septic rat model has been developed and characterized (hemodynamically, metabolically, microbiologically and pathologically) in our laboratory and is appropriate for these investigations, as it exhibits features which parallel human species. The studies will allow comparisons to be made between latent and overt diabetic animals with respect to storage and utilization of carbohydrates. The long term objectives of this project are to understand the causes of carbohydrate dyshomeostasis in sepsis and the causative factors that make diabetics more susceptible to sepsis. These studies will provide a data base upon which to develop specific therapeutic modulities for the treatment of diabetic patients with bacterial infections.